PROJECT SUMMARY Essential tremor (ET) is one of the most prevalent neurological diseases. Although the most recognizable clinical feature of ET is tremor, there is emerging evidence that non-motor features (esp. cognitive dysfunction) may be present. A growing number of studies are showing that ET patients have poorer cognitive performance than age-matched controls, yet the cognitive profile among ET patients with cognitive problems has yet to be fully characterized. In some ET patients, the cognitive problems are quite severe. Recent epidemiological studies have demonstrated that ET patients are more likely to have mild cognitive impairment (MCI) than age-matched controls, and an increased risk of dementia (relative risk = 1.64 - 1.89). While ET appears to be a risk factor for the development of cognitive impairment, the cause of cognitive impairment in ET is not currently known. There is early evidence that ET may be associated with an increased risk of developing disorders characterized by tau pathology. The overall goal of the proposed research is to determine the clinical and pathological characteristics of cognitive impairment associated with ET. To accomplish this goal, we plan to perform neuropsychological examinations during life and post-morbid neuropathological examinations on participants in the Essential Tremor Centralized Brain Repository (ETCBR), a well-characterized sample of 250 elderly ET cases who have all already agreed to brain donation (R01NS042859, E. Louis). While their tremor has been well-characterized, neuropsychological testing has been limited to a gross global cognitive evaluation. A central hypothesis for the proposed research is that the majority of ET patients with MCI and dementia will have disorders characterized by tau pathology (Alzheimer's disease or progressive supranuclear palsy). Our 5-year research proposal has two specific aims: Aim 1: Characterize the cognitive profile and assign diagnoses of normal cognition, MCI, or dementia in 250 ET patients at baseline and every 18 months. Aim 2: Characterize the neuropathological features of 100 brains of patients with ET harvested in Years 1 - 5, including >70 with cognitive impairment. This aim will include neuropathological and biochemical studies to characterize the molecular signature of the tau protein. The study will test several hypothesized clinical and clinical-pathological relationships (Hypotheses 1A-C, 2A-C). We expect that the proposed research will elucidate the processes of dementia in ET and, in due course, shape the counseling and treatment of ET patients with cognitive symptoms. We anticipate that these will be the gold standard data for the study and characterization of cognitive impairment in ET for years to come, and a tissue resource for future investigators.